Cystic renal-epithelial derived induced pluripotent stem cells from polycystic kidney disease patients

Autor: Vanessa J Xavier, Geert J.L.H. van Leenders, Dorien J.M. Peters, Paul C.M.S. Verhagen, Annelies de Klein, Bert Eussen, Job van Riet, Annegien Kenter, Ruben Boers, Harmen J.G. van de Werken, Joost Gribnau, Robert Zietse, Marjan E van Til, Joachim Boers, Gert Jansen, Mehrnaz Ghazvini, Wilfred F. J. van IJcken, Monique Losekoot, Eveline Rentmeester, Ewout J. Hoorn
Přispěvatelé: Cell biology, Developmental Biology, Internal Medicine, Urology, Pathology, Clinical Genetics
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
DNA Mutational Analysis
PKD1
Kidney
urologic and male genital diseases
Epigenesis
Genetic
0302 clinical medicine
Polycystic kidney disease
somatic mutation
Induced pluripotent stem cell
lcsh:R5-920
DNA methylation
lcsh:Cytology
epigenetic memory
General Medicine
Cellular Reprogramming
Polycystic Kidney
Autosomal Dominant
female genital diseases and pregnancy complications
3. Good health
iPS cells
Kidney Tubules
medicine.anatomical_structure
lcsh:Medicine (General)
Reprogramming
Pluripotent Stem Cells
TRPP Cation Channels
Induced Pluripotent Stem Cells
Biology
Cell Line
03 medical and health sciences
Germline mutation
medicine
second hit
Humans
lcsh:QH573-671
ADPKD
cyst
urogenital system
Epithelial Cells
Cell Biology
medicine.disease
renal epithelial cells
030104 developmental biology
Mutation
Cancer research
030217 neurology & neurosurgery
Developmental Biology
Kidney disease
Zdroj: Stem Cells Translational Medicine, 9(4), 478-490. WILEY
Stem cells translational medicine, 9(4), 478-490. John Wiley & Sons Ltd.
Stem Cells Translational Medicine
Stem Cells Translational Medicine, Vol 9, Iss 4, Pp 478-490 (2020)
ISSN: 2157-6564
Popis: Autosomal‐dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure in most patients. In approximately 85% of cases, the disease is caused by mutations in PKD1. How dysregulation of PKD1 leads to cyst formation on a molecular level is unknown. Induced pluripotent stem cells (iPSCs) are a powerful tool for in vitro modeling of genetic disorders. Here, we established ADPKD patient‐specific iPSCs to study the function of PKD1 in kidney development and cyst formation in vitro. Somatic mutations are proposed to be the initiating event of cyst formation, and therefore, iPSCs were derived from cystic renal epithelial cells rather than fibroblasts. Mutation analysis of the ADPKD iPSCs revealed germline mutations in PKD1 but no additional somatic mutations in PKD1/PKD2. Although several somatic mutations in other genes implicated in ADPKD were identified in cystic renal epithelial cells, only few of these mutations were present in iPSCs, indicating a heterogeneous mutational landscape, and possibly in vitro cell selection before and during the reprogramming process. Whole‐genome DNA methylation analysis indicated that iPSCs derived from renal epithelial cells maintain a kidney‐specific DNA methylation memory. In addition, comparison of PKD1+/− and control iPSCs revealed differences in DNA methylation associated with the disease history. In conclusion, we generated and characterized iPSCs derived from cystic and healthy control renal epithelial cells, which can be used for in vitro modeling of kidney development in general and cystogenesis in particular.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Here, we generated induced pluripotent stem cells (iPSCs) of ADPKD patients to study kidney development and cyst formation in vitro. These iPSCs revealed germline and autosomal mutations implicated in ADPKD and displayed an epigenetic memory of kidney epithelial cells, providing powerful models to study ADPKD in vitro.
Databáze: OpenAIRE
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